The concept of using polymers for the controlled release of active drugs and other therapeutic ligands for medical applications has emerged and developed only in the last fifteen to twenty years. Conventionally, active drugs and other agents are administered by periodic application by ingestion of pills, liquids and the like or by injection of the active agent which is then distributed throughout much of the body rather than directed to a specific target area. The difficulties of the conventionally known methods of administration typically arise immediately following the application in which the concentration of the active agent rises to high levels and is distributed system-wide throughout all parts of the body. In some cases, these initially high concentrations produce undesired side effects either at the targeted area requiring the medication or the environments surrounding the targeted area. As time passes after its immediate introduction, the concentration of the active agent begins to fall because of the natural processes of the body which eliminate it from the system, consume it, or degrade it. It has often been found that before the next application of the therapeutic drug is given, the concentration of the active agent has fallen below the necessary level for therapeutic response. In this manner, even periodic applications of the active agent are complicated by concentrations of the active agent which are alternatively either too high or too low within the same dosage period. In addition, such a cyclic regime is rather inefficient in that only a fraction of the entire concentration of active agent introduced into the body reaches the targeted area and performs the intended function.
For these reasons, alternative methods of introducing and controlling the release of active agents have been sought. Much active effort has thus focused on the use of polymeric formulations for the controlled release of active agents using a variety of methods, compositions, and areas of application [Controlled Release Polymeric Formulations, D. R. Paul and F. W. Harris editors, American Chemical Society, Washington, DC 1976]. It has been noted that the function and selection of the polymeric composition suitable for use in a controlled release application should include the following: diffusion and solubility characteristics with the active agents which provide the desired release control; compatibility with the use environment in that the polymer is neither toxic nor antagonistic in medical applications; and compatability with the active agent in that there are no undesirable reactions or physical interactions with the agent.
One of the major problems associated with controlled release polymers and methods is how to combine the active agent with its polymer carrier in a manner which provides a release profile which provides a constant rate of delivery of the active agent over time; by analogy with chemical kinetics, this has become known as a "zero order" process since such a mechanism would not depend on how much of the agent has been delivered or remains attached to the polymer carrier. Bioerodible carriers or polymers rely on the release of the active agent as the polymer carrier is eroded away by the environment through physical processes such as dissolution or by chemical processes such as hydrolysis of the polymer backbone or crosslinks, or by enzymatic degradation. When such polymers are used for delivery of pharmacologically active agents within medical applications, it is essential that the polymers themselves be nontoxic and that they degrade into non-toxic degradation products as the polymer is eroded by the body fluids. However, many synthetic, biodegradable polymers upon erosion in vivo yield oligomers and monomers which often adversely interact with the surrounding tissue [D. F. Williams, J. Mater. Sci. 17:1233 (1982)]. In order to minimize the toxicity of the intact polymer carrier and its degradation products, polymers were designed based upon naturally occurring metabolites. Probably the most extensively studied examples of such polymers are the polyesters derived from lactic or glycolic acid [H. Laufman et al., Surg. Gynecol. Obstet. 145:597(1977); D. L. Wise et al., in Drug Carriers In Biology And Medicine (G. Gregoriadis ed.), Academic Press, London, 1979, pages 237-270] and polyamides derived from amino acids [ D. A. Wood, Int. J. Pharm. 7:1(1980); S. Yolles et al., in Controlled Release Technologies: Methods, Theory, And Applications; A. F. Kydonieus, ed. C.R.C. Press, Boca Raton, Florida, 1980, pages 1-6].
Polyesters based on lactic acid and/or glycolic acid have been shown to be nontoxic and are being used now as bioabsorbable sutures. These polymeric compositions unfortunately erode homogeneously (bulk erosion) which results in uncontrolled and unpredictable release of active agents via unfavorable release kinetics when used for drug release applications. Such "monolithic" systems using these bioerodible polymers share the problem encountered with polyamide polymers which usually show large burst effects and irregular release of active agents when used for control drug delivery. It is now generally accepted that such monolithic bioerodible drug delivery systems demonstrate the desirable "zero-order" release kinetics only if the polymer carrier is hydrophobic enough to erode heterogeneously, that is by surface erosion rather than bulk degradation [J. Heller, in Medical Applications Of Controlled Release (R. S. Langer and D. L. Wise, eds.) C.R.C. Press, Boca Raton, Florida, 1985]. Unfortunately, it is difficult to produce hydrophobic polymeric compositions which degrade by surface erosion and provide the desired release kinetics without themselves being allergenic or toxic or degrading into allergenic or toxic degradation products. Such polymers have remained a soughtafter goal.